In breast oncology, drug therapies, led by the introduction of tamoxifen (TAM), have resulted in significant improvements in survival in women diagnosed with estrogen receptor positive disease. Identifying strategies to further improve the clinical efficacy and/or reduce the known toxicities of these medications is an area of active clinical research. Recent analysis from the PI's K07 Career Development Award in Cancer Prevention and Population Sciences showed a significant 35% reduction in breast cancer recurrence rates in breast cancer survivors who consumed within the highest tertile of cruciferous vegetable intake, a finding unique to the women prescribed TAM. suggesting a favorable diet-drug interaction. This finding is supported by compelling experimental Evidence that diindolylmethane (DIM), an anticarcinogenic compound in cruciferous vegetables, can favorably modulate a number of biological pathways of breast cancer risk. To follow up on these findings we plan to conduct a phase II randomized, placebo-controlled, double-blind intervention trial among 170 premenopausal women taking TAM as adjuvant therapy for breast cancer. We will test the hypothesis that diindolylmethane (BioresponseTM DIM) at a dose of 150 mg/day with a.m. / p.m. dosing for 18 months will result in favorable modulation of breast density (measured using digital mammography and a novel fat-water ratio from MRI) that will be associated with favorable changes in mammary tissue. We also plan to assess women for modulation of estrogen metabolites, endoxifen levels and vaginal bleeding/ultrasound as surrogate biomarkers of efficacy or risk. Our research goal is to test the efficacy and safety of DIM in women taking TAM. This research to identify evidence- based diet-related strategies to significantly improve the efficacy or reduce toxicity of existing pharmaceuticals is an understudied area of translational research. PUBLIC HEALTH RELEVANCE: Tamoxifen therapy is used for the primary prevention of breast cancer and to reduce risk for recurrent disease. Supplementation of the diet with diindolylmethane, a naturally-occurring compound found in cruciferous vegetables, holds potential to improve the efficacy or reduce the toxicity of this medication. If effective, this combinational approach could reduce breast cancer burden for those at risk.